VITamin D and OmegA-3 TriaL (VITAL): Interrelationship of Vitamin D and Vitamin K on Bone

摘要 骨质疏松症是最常见的骨骼疾病; 5360万美国人骨量减少， 增加了他们脆弱性骨折的风险。除了维生素D缺乏症的高患病率外， 研究表明，大约60%的老年男性和40%的老年女性缺乏维生素K。 摄入量越来越多的证据表明，维生素D和维生素C之间存在重要的相互关系。 K在骨头上。维生素D增加肠道钙吸收，刺激两种蛋白质的产生， 骨钙素和基质Gla蛋白。维生素K在激活这些蛋白质中起着重要作用， 骨钙素将钙掺入骨中，基质Gla蛋白抑制软组织中的钙化，包括 肾脏维生素D和K对这些蛋白质的最佳功能都很重要。虽然维生素D 补充剂被广泛用于改善骨骼健康，单独补充维生素D的试验减少了 骨折显示不一致的结果。新出现的证据表明，补充D在低的背景下， 维生素K状况对骨骼健康措施的影响较小。因此，低维生素K状态可能导致 一些测试维生素D和骨骼健康的试验不一致，可能导致毒性 由于高剂量的维生素D，如肾结石。以前没有随机对照试验， 有足够的把握来测试维生素K状态对骨折风险的影响或维生素K状态与 高剂量补充维生素D为了填补知识空白，我们提出了一项创新的辅助研究， 到大型，NIH赞助，维生素D和OmegA-3 TriaL（VITAL）。VITAL正在测试补充剂的效果 维生素D3（胆钙化醇，2000 IU/d）和/或ω-3脂肪酸（鱼油，1 g/d）在一级预防 25，871名美国男性（年龄≥50岁）和女性（年龄≥55岁）中的癌症和心血管疾病，包括5，106名 非裔美国人在这个竞争性的更新应用程序“重要：对骨结构和 架构，”我们将确定是否低维生素K状态，评估3个敏感的生物标志物，修改 补充维生素D对骨折、骨矿物质密度（BMD）和结构的影响，其次是 尿钙排泄增加，是低BMD和肾结石的危险因素。在第一个周期中， 我们超越了招募目标，收集了基线和随机化后2年的影像学研究， 将用于拟定研究的骨密度、结构和体系结构（n=771）。此外，其他 将利用关键的VITAL资源，包括：16，953份基线和6，000份随访血样; 维生素D、钙、肌酐和甲状旁腺激素的测量;以及判定的骨折和肾脏 石头这项提案提供了一个独特的机会，在最大的补充维生素D的研究中澄清， 维生素D和K的相互依赖性及其对骨折、骨骼健康指标和尿液的作用 钙排泄拟议的辅助研究的结果对于解释正在进行的 维生素D试验，并提供新的见解，以推进临床护理和公共卫生建议。

ABSTRACT Osteoporosis is the most common bone disease; 53.6 million Americans have a reduced bone mass, which increases their risk of fragility fractures. In addition to the high prevalence of vitamin D deficiency, recent studies show that approximately 60% of older men and 40% of older women have inadequate vitamin K intakes. Growing evidence indicates that there are important interrelationships between vitamin D and vitamin K on bone. Vitamin D increases intestinal calcium absorption and stimulates production of two proteins, osteocalcin and matrix Gla protein. Vitamin K plays an essential role in activating these proteins so that osteocalcin incorporates calcium in bone and matrix Gla protein inhibits calcification in soft tissues, including the kidney. Both vitamins D and K are important for optimal function of these proteins. Although vitamin D supplements are widely used to improve bone health, trials of supplemental vitamin D alone in reducing fractures showed inconsistent results. Emerging evidence indicates that supplemental D in the context of low vitamin K status is less effective on bone health measures. Therefore, low vitamin K status may account for some of the inconsistencies of trials testing vitamin D and bone health and may contribute to toxicities attributed to high-dose vitamin D such as kidney stones. No previous randomized controlled trials have been adequately powered to test effects of vitamin K status on fracture risk or the interaction of vitamin K status with high-dose, supplemental vitamin D on bone. To fill knowledge gaps, we propose an innovative, ancillary study to the large, NIH-sponsored, VITamin D and OmegA-3 TriaL (VITAL). VITAL is testing effects of supplemental vitamin D3 (cholecalciferol, 2000 IU/d), and/or omega-3 fatty acids (fish oil, 1 g/d) in the primary prevention of cancer and cardiovascular disease in 25,871 U.S. men (aged ≥50) and women (aged ≥55), including 5,106 African Americans. In this competitive renewal application of “VITAL: Effects on Bone Structure and Architecture,” we will determine whether low vitamin K status, assessed by 3 sensitive biomarkers, modifies effects of supplemental vitamin D on fractures, bone mineral density (BMD) and structure, and secondarily on increases in urine calcium excretion, a risk factor for low BMD and kidney stones. During the first cycle of this grant, we surpassed recruitment goals and collected baseline and 2-yr post-randomization imaging studies for bone density, structure and architecture that will be used in the proposed studies (n=771). In addition, other key VITAL resources will be leveraged including: 16,953 baseline and 6,000 follow-up blood samples; measures of vitamin D, calcium, creatinine and parathyroid hormone; and adjudicated fractures and kidney stones. This proposal provides a unique opportunity to clarify in the largest study of supplemental vitamin D, the interdependencies of vitamins D and K and their roles on fractures, bone health measures, and urine calcium excretion. Findings from the proposed ancillary study will be critical to the interpretation of on-going vitamin D trials and provide new insights to advance clinical care and public health recommendations.